Targeting the PD-1 Pathway for HIV Eradication?

The blockade of PD-1/PD-L1 interaction represents a promising therapeutic strategy for reactivation of virus-specific effector T cells to exert pathogen eradication in chronic viral infections like HIV. The first clinical trials are waiting the green light to start.

Programmed Death-1 (PD-1) is a negative regulator of T cell activation and proliferation that mediates suppressive action by binding to its ligands PD-L1 and PD-L2.

T cell exhaustion is a state of T cell dysfunction that arises during many chronic infections and cancer.

Over the last few years, it has been established that PD-1 plays an active and reversible role in T cell exhaustion.

Under physiological conditions, PD-1 is induced after T cell activation and serves as an inhibitory feedback to dampen the TCR signalling cascade and prevent excessive T cell activation. PD-1 plays also an important role in the tolerance to self antigens.

Expression of PD-1 ligands is elevated in HIV infection in an effort to reduce ongoing inflammation.

HIV can also directly up-regulate the expression of PD-1 ligands on antigen presenting cells leading to an impairment of these cells’ function and, as a consequence, of HIV specific immune responses.

Increased PD-1 expression has also been correlated with worse immune reconstitution during ART.

PD-1, on the other hand, may also contribute to the maintenance of latent HIV in memory CD4 T cells.

Immunotherapy based on the blockade of PD-1/PD-L1 interaction represents a promising therapeutic strategy for reactivation of virus-specific effector T cells to exert pathogen eradication in chronic HIV infection and also further purge the remaining viral reservoir.

The first clinical trial using anti PD-1 antibodies is under approval and ready to start.

This trial will have to answer a couple of questions:

-Is PD-1 blockade safe in HIV-infected patients?

-Does PD-1 blockade enhance HIV specific immune responses?

-Does PD-1 blockade allows a better immune reconstitution than what is obtained with ART alone?